• Rituxan® (rituximab)
Oral P13K Delta Inhibitor
|INDICATION||COMBINATION||CLINICAL PROOF OF CONCEPT||MARKETING APPROVAL STUDY||COMMERCIAL RIGHTS|
1 Phase 2 study to support an accelerated approval marketing application with FDA
2 Study arm initiated under clinical collaboration with BeiGene, Ltd.
ME-401 is an oral, once-daily, selective inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ) in clinical development for the treatment of B-cell malignancies. MEI owns worldwide rights to ME-401 in all geographies except Japan, which we licensed to Kyowa Kirin Co., Ltd. in 2018.
We are conducting a global Phase 2 study of ME-401 as a monotherapy for the treatment of adults with relapsed or refractory (r/r) follicular lymphoma (FL). Upon completion of the Phase 2 clinical trial we are planning a submission with the Food and Drug Administration (FDA) to support an accelerated approval of a marketing application. Also ongoing is a multi-arm, open-label, Phase 1b dose escalation and expansion trial evaluating ME-401 as a monotherapy and in combination with other therapies or investigational agents in patients with r/r B-cell malignancies.
PI3Kδ inhibitors are validated for the treatment of B-cell malignancies, but first-generation drugs are challenged by dose-limiting toxicities that restrict clinical utility. This presents an opportunity for the development of a next-generation candidate with pharmaceutical properties that can maintain clinical utility while potentially minimizing the immune-related adverse events which have limited their use.
To that end, the pharmaceutical properties of ME-401 allow exploration of flexible dosing regimens such as an intermittent dosing schedule, which has the potential to maintain clinical benefit while minimizing immune-related toxicities common to other PI3Kδ agents, either as a monotherapy or in combination with other therapies or investigational agents.
MECHANISM OF ACTION
The PI3K/AKT/mTOR pathway is an important signaling pathway for many cellular functions such as cell survival, cell cycle progression and cellular growth. The PI3K family of enzymes within this pathway have been shown to play a critical role in the proliferation and survival of certain cancer cells. There are several isoforms of PI3K that are expressed in different types of cells; the delta isoform is often overexpressed in cancer cells and is understood to be important for survival of certain B-cell leukemias and lymphomas.
ME-401 displays high selectivity for the PI3K delta isoform and has distinct pharmaceutical properties from other PI3K delta inhibitors.
ABOUT B-CELL MALIGNANCIES
B-cell malignancies are those starting in B lymphocytes, a type of white blood cell. They include both slow growing (indolent) diseases as well as aggressive diseases and represent a collection of different blood cancers. Examples include chronic lymphocytic leukemia, follicular lymphoma, mantle cell lymphoma and diffuse large B-cell lymphoma.
Phase 1b Study
An ongoing Phase 1b study in patients with r/r FL and other B-cell malignances is evaluating ME-401 as a monotherapy and in combination with rituximab or zanubrutinib, a Bruton Tyrosine Kinase (BTK) inhibitor developed by BeiGene, Ltd. Evaluation of the ME-401 and zanubrutinib combination is being conducted under a clinical collaboration agreement with BeiGene.
Patients in the Phase 1b study are administered ME-401 once daily at 60 mg for two 28-day cycles and then on an intermittent schedule of once daily dosing for the first 7 days of each subsequent 28-day cycle (i.e. the intermittent schedule or IS). A previous cohort of monotherapy patients in the study was treated with ME-401 administered continuously once daily or were switched to IS after Cycle 2 was completed (i.e. the continuous schedule or CS).
In October 2019, we reported updated interim data from the Phase 1b clinical trial. Over 95 patients were enrolled at the time of the update, of which 73 patients with r/r FL or r/r chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) patients were evaluable for efficacy. Data demonstrated that ME-401 achieved a high overall response rate of 81% among all evaluable FL and CLL/SLL patients. The overall response rate was 78% and 89% in the 55 and 18 patients with FL or CLL/SLL, respectively. Similarly high rates of response and durability were observed in patients administered ME-401 on the IS and CS regimens.
ME-401 was well-tolerated and no grade 4 or grade 5 adverse events of special interest have been observed in the Phase 1b trial. Among drug related grade 3 adverse events of special interest, the most common was diarrhea/colitis at 5.0% (3/57) on IS dosing and 23% (9/39) on CS dosing. Patients on the IS dosing regimen showed significantly improved overall tolerability.
Phase 2 Study to Support Accelerated Approval with U.S. FDA
We are conducting the TIDAL study (Trials of PI3K DeltA in Non-Hodgkin's Lymphoma), a global Phase 2 study evaluating ME-401 as a monotherapy for the treatment of adults with r/r FL after failure of at least two prior systemic therapies including chemotherapy and an anti-CD20 antibody. Subject to the results, upon completion of the Phase 2 clinical trial, we are planning a submission with FDA to support an accelerated approval of a marketing application under 21 CFR Part 314.500, Subpart H.
Two ME-401 oral dosing regimens are being evaluated; ME-401 60 mg once daily continuously and ME-401 60 mg once daily continuously for two cycles (i.e. 8 weeks) followed by the intermittent schedule, in which ME-401 is administered 60 mg once daily for the first seven days of a 28 day cycle followed by three weeks of 60 mg placebo. Approximately 150 evaluable patients will be randomized in the study and the primary efficacy endpoint will be the rate of objective response to therapy.
This two-arm study design allows further evaluation of the safety and efficacy of dosing regimens evaluated in the Phase 1b study. Data from the ongoing Phase 1b study suggests that the intermittent schedule has a high observed response rate and may reduce the incidence of adverse events of special interest.